Derivatives of azetidine and pyrrolidine

ABSTRACT

The invention relates to a compound having formula (I) wherein A is an optionally unsaturated 5- or 6-membered ring, which may comprise a heteroatom selected from N, O and S and which may be substituted with oxo or (1-6C)alkyl; R 1 , R 2  and R 3  are independently H, (1-6C)alkyl, (1-6C)alkoxy, (1-6C)alkoxy(1-6C)-alkyl, carbo(1-6C)alkoxy or halogen; X is O or S; and n is 1 or 2; or a pharmaceutically acceptable salt thereof, with the exception of 3-(naphth-1-yl-oxy)-pyrolidin and 3-(5,6,7,8-tetmhydro-naphth-1-yl-oxy)-pyrolidin. The compounds of the invention have antidepressant activity and can be used in treating or preventing serotonin-related diseases.

This application is a 371 of PCT/EP98/01282 Feb. 26, 1998.

The invention relates to derivatives of azetidine and pyrrolidine, topharmaceutical compositions comprising the same, a process for theirpreparation, as well as the use of derivatives of azetidine andpyrrolidine for the preparation of a medicament which acts on thecentral nervous system.

In recent years the contribution of serotonergic activity to the mode ofaction of antidepressant drugs has been well documented and compoundswhich enhance activity in the serotonin system have been developed andsuccessfully introduced as antidepressants. Serotonin reuptakeinhibitors (SRI) work by increasing the amount of serotonin available atthe synapse. Although the SRI's have more favourable side effectprofiles than previous generations, they are not devoid of side effectsand still suffer from a slow onset of action [Andrews and Nemeroff,“Contemporary management of depression”—American Journal of Medicine97(6A): 24S-32S (1994); Leonard, “The comparative pharmacology of newantidepressants”—Journal of Clinical Psychiatry 54(Suppl): 3-15 (1993)].Moreover, the mechanism of action of the SRI's although specific forserotonin, is not selective in that they effect activity at a multitudeof different serotonin receptor subtypes. This broad spectrum ofactivity may lead to many of the side effects associated with the SRI'se.g. nausea from activation of 5-HT3, headache due to activation of5-HT2B. Thus, SRI's can alter the function of several 5-HT2 receptorsubtypes, however, the efficacy of these drugs may correlate moststrongly with their effects on the 5-HT2C system [(Broekkamp andBerendsen “The importance of 5-HT1C receptors for anti-depressanteffects”—Polish Journal of Pharmacology and Pharmacy 44(Suppl): 20(1992); Cesana et al “Mesulergine antagonism towards the fluoxetineanti-immobility effect in the forced swimming test in mice”—Journal ofPharmacy and Pharmacology 45: 473-475 (1993); Berendsen and Broekkamp“Comparison of stimulus properties of fluoxetine and 5-HT receptoragonists in a conditioned taste aversion procedure”—European Journal ofPharmacology 253: 83-89 (1994)]. These data suggest that compounds whichselectively activate the 5-HT2C receptor will be effective in thetreatment of affective disorders and related conditions.

The invention relates to compounds according to the formula I

wherein A is an optionally unsaturated 5- or 6-membered ring, which maycomprise a heteroatom selected from N, O and S and which may besubstituted with oxo or (1-6C)alkyl; R¹, R² and R³ are independently H,(1-6C)alkyl, (1-6C)alkoxy, (1-6C)alkoxy-(1-6C)alkyl, carbo(1-6C)alkoxyor halogen; X is O or S; and n is 1 or 2; or a pharmaceuticallyacceptable salt thereof, with the exception of3-(naphth-1-yl-oxy)-pyrrolidir and3-(5,6,7,8-tetrahydro-naphth-1-yl-oxy)-pyrrolidin. The compounds have aselective effect on 5-HT2C receptors in the central nervous sytem.

In U.S. Pat. No. 4,452,809 [filed Apr. 22, 1983]3-aryloxy-4-hydroxypyrrolidines were disclosed, wherein it was foundthat 3-naphthyl or 3-indenyloxy-4-hydroxypyrrolidines haveantiarrhythmic activity, whereas 3-phenoxy-4-hydroxypyrrolidines werefound to have antidepressant activity. Some years earlier, in DT2,738,477 [priority date Sep. 1, 1977] also3-aryloxy-4-hydroxypyrrolidines were disclosed, wherein the preferredcompounds with antidepressant activity were also 3-phenoxy derivatives.Other 3-aryloxypyrrolidines wherein the pyrrolidine-group of allcompounds is N-substituted, having an effect on the serotonin receptor,were disclosed in EP 0,338,331 [priority date Apr. 19, 1988].

Surprisingly, after many years of research, it has now been found, thatthe compounds of formula I, (bicyclic aryl)oxy-substituted pyrrolidinesand (bicyclic aryl)oxy-substituted azetidines wherein the 5- or4-membered heterocycle is not substituted at any position in the ring,have a selective effect on 5-HT2C receptors in the central nervoussytem. Also the compounds 3-(naphth-1-yl-oxy)-pyrrolidin and3-(5,6,7,8-tetrahydro-naphth-1-yl-oxy)-pyrrolidin, known asintermediates but not claimed in EP 0,338,331, were found to have thiseffect. Therefore, also protection is sought for the use of thesecompounds and for pharmaceutical compositions comprising them. Thus, theinvention also pertains to the first medical use of the compoundsaccording to formula 1, i.e. including the compounds3-(naphth-1-yl-oxy)-pyrrolidin,3-(5,6,7,8-tetrahydro-naphth-1-yl-oxy)-pyrrolidin for use as amedicament (or, in other words, for use in therapy).

The use of a selective 5-HT2C agonist ensures that pharmacologicalactivity occurs immediately and preferentially at the 5-HT2C receptorsallowing a much quicker onset of selective pharmacological activationthan can be observed with SRI's. Moreover the selectivity of thecompound reduces the potential for adverse effects mediated by otherserotonin receptors e.g. nausea, headache, effects which may hindercompliance and thus interfere with efficacy.

The compounds of the present invention act on the central nervoussystem, in particular as antidepressants, and against obsessivecompulsive disorders, anxiety disorders including generalised anxiety,panic attacks, agoraphobia, eating disorders such as obesity, urinaryincontinence, impotence, aggression and drug abuse such as alcohol ornarcotic addiction.

Preferred compounds according to the invention have the formula Iwherein the heteroatom in A, if present, is N or S; R¹ is H,(1-6C)alkyl, (1-6C)alkoxy, (1-6C)alkoxy-(1-6C)alkyl; R² is H,(1-6C)alkoxy, carbo(1-6C)alkoxy or halogen and R³ is H, (1-6C)alkyl,(1-6C)alkoxy or halogen.

More preferred are compounds of the formula (Ia)

wherein A is an unsubstituted saturated 5-membered or optionallyaromatic 6-membered ring, which may comprise a nitrogen atom adjacent tothe position indicated with an asterisk; R¹ is H or (1-6C)alkoxy; R² isH, (1-6C)alkoxy or halogen; R³ is H or halogen; and n is 1 or 2. Morepreferred are the compounds of formula (Ia) wherein A is anunsubstituted saturated 5-membered or optionally aromatic 6-memberedring; R¹ is (1-6C)alkoxy and R² and R³ are H. Most preferrably, A informula (Ia) is a 5-membered ring and R¹ is methoxy, in particular whenn is 2.

The term (1-6C)alkyl means a branched or unbranched alkyl group having 1to 6 carbon atoms, such as methyl, ethyl, t-butyl, isopentyl, and thelike. The most preferred alkyl group is methyl.

The term (1-6C)alkoxy means an alkoxy group having 1-6 carbon atoms, thealkyl moiety of which having the meaning as previously defined. The mostpreferred alkoxy group is methoxy.

The term halogen means fluorine, chlorine or bromine.

The compounds according to formula I may be prepared in a mannerconventional for such compounds. To that end, compounds of generalformula II, wherein A, R₁, R², R³, X and n are as previously defined andP is any N-protecting group, stable under alkaline conditions [suitableN-protecting groups can be found in T. W. Green and P. G. M. Wuts:Protective Groups in Organic Synthesis, Second Edition (Wiley, NY,1991)], are deprotected using the appropriate conditions such ascatalytic hydrogenation or intermediate carbamate formation, followed byreaction with alcohols. Optionally at the same time, a salt may beformed.

The compounds according to general formula II may be prepared byarylether formation of suitable N-protected 3-hydroxy-azetidines or-pyrrolidines, wherein the protecting group is as hereinbefore defined,with appropriately substituted aromatic or heteroaromatic compoundsbearing a suitable leaving group. Alternatively, N-protected-azetidinesor -pyrrolidines bearing a suitable leaving group at the 3-position,such as halogen, triflate, tosylate or mesylate, can be reacted withappropriately substituted aromatic or heteroaromatic compounds bearing ahydroxy, or mercapto group.

The compounds of the invention, which can be in the form of a free base,may be isolated from the reaction mixture in the form of apharmaceutically acceptable salt. The pharmaceutically acceptable saltsmay also be obtained by treating the free base of formula I with anorganic or inorganic acid such as hydrogen chloride, hydrogen bromide,hydrogen iodide, sulfuric acid, phosphoric acid, acetic acid, propionicacid, glycolic acid, maleic acid, malonic acid, methanesulphonic acid,fiumaric acid, succinic acid, tartaric acid, citric acid, benzoic acid,ascorbic acid and the like.

The compounds of this invention may possess one or more chiral carbonatoms, and may therefore be obtained as a pure enantiomer, or as amixture of enantiomers, or as a mixture containing diastereomers.Methods for obtaining the pure enantiomers are well known in the art,e.g. crystallization of salts which are obtained from optically activeacids and the racemic nixture, or chromatography using chiral columns.

The compounds of the invention may be administered enterally orparenterally, and for humans preferably in a daily dosage of 0.001-100mg per kg body weight, preferably 0.01-10 mg per kg body weight. Mixedwith pharmaceutically suitable auxiliaries, e.g. as described in thestandard reference, Gennaro et al., Remington's Pharmaceutical Sciences,(18th ed., Mack Publishing Company, 1990, see especially Part 8:Pharmaceutical Preparations and Their Manufacture) the compounds may becompressed into solid dosage units, such as pills, tablets, or beprocessed into capsules or suppositories. By means of pharmaceuticallysuitable liquids the compounds can also be applied in the form of asolution, suspension, emulsion, e.g. for use as an injectionpreparation, or as a spray, e.g. for use as a nasal spray. For makingdosage units, e.g. tablets, the use of conventional additives such asfillers, colorants, polymeric binders and the like is contemplated. Ingeneral any pharmaceutically acceptable additive which does notinterfere with the function of the active compounds can be used.

Suitable carriers with which the compositions can be administeredinclude lactose, starch, cellulose derivatives and the like, or mixturesthereof, used in suitable amounts.

The invention is further illustrated by the following examples.

EXAMPLES Experimental

General Methods

A first general process step consists of the preparation of a suitableN-protected-3-hydroxy-azetidine and -pyrrolidine and subsequentarylether formation. Any protective group, stable under alkalinecoupling conditions will do. This applies also for the pyrrolidinesseries, where a benzyl group is found to be the, best accessible andmost convenient protective group. As for the azetidines a bulky groupsuch as triphenylmethyl, 4,4′-disubstituted diphenylmethyl,α-methylbenzyl and, as a matter of choice, diphenylmethyl can be usedfor the ease of azetidine ring formation during synthesis. Thesecompounds may be prepared by reacting the corresponding primary amnineswith epichlorohydrine in a polar solvent such as methanol ordimethylformamnide at elevated temperatures ranging from roomtemperature to reflux, usually over a period of several days.

The N-protected-3-hydroxy-azetidines and -pyrrolidines can be used assuch in a condensation reaction with a wide variety of compounds bearinga suitable leaving group on an aromatic moiety to get ether formation.When the leaving group is for instance halogen the reaction can beperformed in a polar solvent such as dimethylformamide and a suitablebase, for example potassium carbonate in the presence of a catalyst likeactivated copper, at elevated temperatures ranging from room temperatureup to reflux temperature.

In a preferred second general process step the hydroxy group of theN-protected-3-hydroxy-azetidines and -pyrrolidines is converted, bymethods well known to a skilled person, into a reactive leaving groupsuch as for instance halogen, triflate , tosylate and, for choice,mesylate, followed by a condensation reaction with a wide variety ofcompounds bearing an aromatic hydroxy (or mercapto) group to get a widevariety of aryl ethers, as well as aryl thioethers.

The mesylates are conveniently prepared by the addition ofmethanesulfonylchloride to the 3-hydroxy compounds in an apolar solventsuch as toluene in the presence of an organic base like triethylamine ata temperature of −30° C. up to reflux temperature, usually at reducedtemperature.

Although all common aryl-alkyl ether formation reactions known fromliterature may be applicable, most compounds were prepared according tothree main procedures.

(I) A first general applicable preparation consist of a heterogeneoustwo phase reaction between mesylate and an appropriate nucleophile,preferably a bicyclic compound containing an aromatic hydroxy ormercapto group. The two phase system consists of an aqueous solution ofan inorganic base such as sodium hydroxide and an organic layer,preferably 4-methyl-2-pentanone. The reaction is performed at atemperature of 25° C. up to reflux temperature, preferably at elevatedtemperature.

(ii) A second preparation consists of a condensation reaction of bothsubstrates, mesylate and nucleophile, in a polar organic solvent such astert-butanol or dimethylsulfoxide or mixtures thereof and a suitablebase like potassium tert-butoxide, generally at elevated temperaturesranging from 25° C. up to 100° C.

(iii) A third preparation consists of anion formation by a base likesodium hydride and subsequent reaction with mesylate in a polar solventsuch as dimethylformamide, usually at elevated temperatures ranging from25° C. up to reflux.

A third general process step concerns all types of deprotection methodsresulting in (cyclic) secondary amines. All convential methods withregard to the selected protective group, well known to a skilled person,must be taken in consideration. As for the aralkyl groups commonly usedin this invention two types of deprotection methods are preferred. Thefirst method consists of the removal of the protective group bycatalytic hydrogenation at a pressure varying from atmospheric to 60 psiin a polar solvent such as ethanol or methanol in the presence of acommonly used catalyst such as palladium on activated carbon orpalladium hydroxide on carbon at a temperature of 25-60° C. A secondmethod consist of the replacement of the original protective group by anintermediate carbamate function which on turn is removed afterwards.Suitable reagents are for instance 1-chloroethyl chloroformate or vinylchloroformate in an aprotic solvent such as 1,2-dichloroethane at atemperature of −15° C. up to reflux temperature and subsequent reactionwith an alcohol such as methanol or ethanol at a temperature of −15° C.up to reflux temperature.

A fourth general process step concerns the preparation or separarationof stereoisomers, including diastereomers and enantiomers, as aconsequence of the presence of one or more centres of chirality.

Enantio selective preparations can be performed starting from enantiopure (R) and (S) substrates such as for instance (R)- or(S)-1-benzyl-3-pyrrolidinol.

The individual enantiomers may also be obtained from a mixture ofstereoisomers using any method well known in the art for separating suchisomers into their constituent enantiomers. For example, using methodsdescribed in Stereochemistry of Organic compounds, E. L. Eliel and S. H.Wilen, chapter 7, 1994. In particular by methods such as salt formationwith optically active acids followed by fractional crystallisation or bydifferential absorption using columns packed with chiral material, forexample chiral liquid or gas chromatography.

A fifth general process step includes the conversion of the secondaryand tertiary amines prepared during synthesis into any salt or solvateform, preferably pharmaceutically accepted salts and solvates such ashydrochloride salts, namely prepared by addition of the acid of choiceto the free base in a solvent like ethanol and isolation as a solid.

PREPARATION OF STARTING MATERIALS (azetidine substrates)

Smooth procedure suitable for large scale production of both1-(diphenylmethyl)-3-azetidinol and its methanesulfonate (modificationof U.S. Pat. No. 4,183,923 E. H. Gold et. al. January 1980):

1-(Diphenylmethyl)-3-azetidinol

Under nitrogen diphenylmethylamine (34.5 ml) was added to a solution ofepichlorohydrine (34.7 ml) in 1 L of anhydrous dimethylformamide. Thereaction mixture was heated at 95° C. for 64 hours. Afterwards it wascooled to 5° C. and a mixture of 20 ml of concentrated aqueoushydrochloric acid and 20 ml of water was added dropwise. Afterevaporation in vacuo the residue was stirred with diethyl ether andfiltered. The solid was washed with diethyl ether and then partitionedbetween diethyl ether and a 2N aqueous sodium hydroxyde solution. Theorganic layer was dried over sodium sulfate, filtered and concentratedin vacuo. The residue was crystallized from a mixture of toluene andpetrol ether to give 36.3 g of 1-(diphenylmethyl)-3-azetidinol, m.p.107° C.

1-(Diphenylmethyl)-3-methanesulfonyloxy-azetidine

Under nitrogen methanesulfonylchloride (7.8 ml) was dropped slowly intoa suspension of 1-(diphenylmethyl)-3-azetidinol (29.3 g) andtriethylamine (14 ml)in 220 ml of dry toluene at a temperature of 15° C.The temperature was allowed to raise to room temperature slowly and thereaction mixture was stirred for 17 hours. Then 220 ml of dry diethylether were added and the precipitated triethylamine hydrochloride wasfiltered and washed with a diethyl ether/dichloromethane mixture (4:1).The organic layer was washed with 100 ml of a 1.1M sodium bicarbonatesolution and then with brine. It was dried over sodium sulfate filteredand evaporated in vacuo to give 29.4 g of1-(diphenylmethyl)-3-methanesulfonyloxy-azetidine, M.S. (C.I.) (M/Z):318 [M+H]⁺.

PREPARATION OF OTHER STARTING MATERIALS

5-Chloro-2,3-dihydro-1H-inden-4-ol (Step a, b, c)

a) 3-Chloro-propanoic acid 2-chlorophenyl ester3-chloropropionylchloride (14 ml) was added to 2-chlorophenol (18.18 g)and the mixture was stirred and heated at 60° C. for 1 hour, at 75° C.for 1 hour and left over the weekend at ambient temperature. Thecompound was purified by destination in vacuo to give 19,7 g (b.p.91-94° C. 0.08 mm Hg) of 3-chloro-propanoic acid 2-chlorophenyl ester.

b) 6-Chloro-2,3-dihydro-7-hydroxy-1H-inden-1-one To 3-chloro-propanoicacid 2-chlorophenyl ester (19.6 g) was added 1 equivalent of aluminumchloride (11.93 g) and the mixture was stirred under nitrogen for 2.5hours at 100° C., cooled, a second portion of aluminum chloride (14 g)added, and heated at 170° C. for 2 hours.

The reaction mixture was cooled to 70-80° C. and water was addedcarefully. Then ethyl acetate was added while stirring and the layersseparated. The ethyl acetate solution was washed with water, dried overmagnesium sulfate, filtered and concentrated in vacuo. A solid separatedwhich was removed by filtration and the remaining filtrate wasevaporated untill dryness. The residue was chromatographated over silicausing toluene as the eluent giving 3.2 g of6-chloro-2,3-dihydro-7-hydroxy-1H-inden-1-one, M.S. (C.I.) (M/Z): 183[M+H]⁺.

c) 5-Chloro-2,3-dihydro-1H-inden-4-ol 3.2 g of6-chloro-7-hydroxy-1H-inden-1-one in 16.8 ml of water and 67.2 ml ofconcentrated aqueous hydrochloric acid were stirred and heated withfreshly prepared zinc amalgame (from 26.88 g of zinc wool) in an oilbath at 120° C. for 16 hours. The reaction mixture was cooled, decantedand treated with ethylacetate and dichloromethane. The organic layer wasevaporated in vacuo. The residue was purified by an acid/base separationyielding 2.08 g of 5-chloro-2,3-dihydro-1H-inden-4-ol, M.S. (C.I.)(M/Z): 169 [M+H]⁺.

In an analogues manner 2,3-Dihydro-5-methyl-1H-inden-4-ol, M.S. (C.I.)(M/Z): 149 [M+H]⁺ was prepared, starting from 3-chloro-propanoic acid2-methylphenyl ester.

2,3-Dihydro-5-methoxy-1H-inden-4-ol (Step a, b, c, d)

a) 3-(2,3-Dimethoxyphenyl)-propanoic acid Nitrogen was passed through astirred suspension of (Z)-3-(2,3-dimethoxyphenyl)-2-propenoic acid(14,67 g) in 400 ml of methanol during 15 minutes. Then 1.4 g of 10%palladium on activated carbon were added and a stream of hydrogen waspassed through the reaction mixture for 16 hours. After removing thepalladium catalyst by filtration, the filtrate was evaporated to yield14.2 g of 3-(2,3-dimethoxyphenyl)-propanoic acid, M.S. (C.I.) (M/Z): 211[M+H]⁺.

b) 2,3-Dihydro-4,5-dimethoxy-1H-inden-1-one Under nitrogen a solution of3-(2,3-dimethoxyphenyl)-propanoic acid (2 g) in 50 ml methanesulfonicacid was warmed at 60° C. and kept there for 2 hours. The reactionmixture was cooled to room temperature and poured into ice/water. Afterextraction with ethyl acetate the organic layer was washed with a 1Naqueous sodium hydroxyde solution, dried over magnesium sulfate,filtered and evaporated in vacuo yielding 1.2 g of2,3-dihydro-4,5-dimethoxy-1H-inden-1-one, M.S. (C.I.) (M/Z): 193 [M+H]⁺.

c) 2,3-Dihydro-4-hydroxy-5-methoxy-1H-inden-1-one Under a nitrogenatmosphere 2,3-dihydro-4,5-dimethoxy-1H-inden-1-one (31.7 g) wasdissolved in 600 ml of anhydrous 1,2-dichloroethane and cooled to 0° C.Aluminum chloride (44 g) was added in portions and the reaction mixturewas heated to 60° C. for 17 hours, cooled to room temperature and pouredinto ice/water. After extraction with dichloromethane the organic layerwas dried and evaporated. The residue was crystallized from ethylacetate to give 20.5 g of2,3-dihydro-4-hydroxy-5-methoxy-1H-inden-1-one, M.S. (C.I.) (M/Z): 179[M+H]⁺.

d) 2,3-Dihydro-5-methoxy-1H-inden-4-ol The 20.5 g of2,3-dihydro-4-hydroxy-5-methoxy-1H-inden-1-one were suspended in amixture of 310 ml of concentrated aqueous hydrochloric acid and 53 ml ofwater. Freshly prepared zinc amalgame (from 87 g of zinc wool) was addedand the mixture was stirred for 3 hours at ambient temperature. Afterdecantation the resting zinc amalgame was washed three times withdiethyl ether and the acidic water solution was extracted with diethylether. The combined ether solutions were washed with a 1N aqueoushydrochloric acid solution, dried over magnesium sulfate, filtered andevaporated in vacuo to afford 15.0 g of2,3-dihydro-5-methoxy-1H-inden-4-ol, M.S. (C.I.) (M/Z): 165 [M+H]⁺.

6-Fluoro-1-methyl-1H-inden-4-ol (Step a, b, c)

a) 4-Chloro-butanoic acid 3-fluorophenyl ester 4-Chlorobutyrylchloride(35.3 g) was added to 3-fluorophenol (25 g). This mixture was stirredduring 48 h at room temperature. After the reaction was completed theproduct was purified by vacuo-destillation. Yield: 35,3 g (b.p. 106° C.3 mmHg) of 4-chloro-butanoic acid 3-fluorophenyl ester as a white oil.

b) 5-Fluoro-2,3-dihydro-7-hydroxy-3-methyl-1H-inden-1-one After theobtained 4-chloro-butanoic acid 3-fluorophenyl ester (35.33 g) washeated to 80° C., aluminium chloride (24.0 g) was added. The reactionmixture started to foam. After the foaming was reduced the mixture wasstirred during 2 hours at 100° C. After cooling water and ethyl acetatewere added and the mixture was heated on a steam bath. After all the oilwas dissolved the organic layer was separated and washed with water andbrine. The solvent was removed and the residue was crystallized from2-propanol to give 21.2 g of5-fluoro-2,3-dihydro-7-hydroxy-3-methyl-1H-inden-1-one, M.S. (C.I.)(M/Z): 181 [M+H]⁺.

c) 6-Fluoro-2,3-dihydro-1-methyl-1H-inden-4-ol 5 g of5-fluoro-2,3-dihydro-7-hydroxy-3-methyl-1H-inden-1-one was heated to 80°C. until all the solid was melted. After adding aluminium chloride (9.3g) to this melt the reaction mixture was heated to 170° C. during 17hours. After cooling water and ethyl acetate were added and the mixturewas heated on a steam bath until everything was dissolved. The organiclayer was separated and washed with water and brine. After removing thesolvent the compound was purified by chromatography with the add ofheptane/ethylacetate (9:1) resulting in 2.2 g of6-fluoro-2,3-dihydro-1-methyl-1H-inden-4-ol as a semi-solid, M.S. (C.I.)(M/Z): 167 [M+H]⁺.

PREPARATIONS Example 1

3-[(5-Chloro-2,3-dihydro-1H-inden-4-yl)oxy]-1-(diphenylmethyl)-azetidine

a) 2 g of 5-chloro-2,3-dihydro-1H-inden-4-ol were stirred in 75 ml of a2N sodium hydroxyde solution for 1 hour. To the clear solution wereadded 75 ml of 4-methyl-2-pentanone and 3.76 g of1-(diphenylmethyl)-3-methanesulfonyloxy-azetidine and the mixture washeated in an oil bath at 120° C. for 3.5 hours. Then another 2 g ofmesylate were added and heating was continued for 64 hours. The upperlayer was separated and washed with water. Evaporation in vacuo andchromatography with toluene/ethyl acetate (95:5) gave 4.22 g of3-[(5-chloro-2,3-dihydro-1H-inden-4-yl)oxy]-1-(diphenylmethyl)-azetidineas a clear oil that solidified spontaneous. M.S. (C.I.) (M/Z): 391[M+H]⁺.

In a similar way were prepared:

b) 3-[(2,4-Dichloro-1-naphtalenyl)oxy]-1-(diphenylmethyl)-azetidine,M.S. (C.I.) (M/Z): 435 [M+H]⁺, starting from 2,4-dichloro-1-naphtol,

c) 1-(Diphenylmethyl)-3-[(4-methyl-1-naphtalenyl)oxy]-azetidine, M.S.(C.I.) (M/Z): 380 [M+H]⁺, starting from 4-methyl-1-naphtol,

d) 1-(Diphenylmethyl)-3-[(2-methoxy-1-naphtalenyl)oxy]-azetidine, M.S.(C.I.) (M/Z):396 [M+H]⁺, starting from 2-methoxy-1-naphtol,

e)1-(Diphenylmethyl)-3-[(5,6,7,8-tetrahydro-1-naphtalenyl)oxy]-azetidine,M.S. (C.I.) (M/Z): 370 [M+H]⁺, starting from5,6,7,8-tetrahydro-1-naphtol,

f)1-(Diphenylmethyl)-3-[(2,3-dihydro-5-methoxy-1H-inden-4-yl)oxy]-azetidine,M.S. (C.I.) (M/Z): 386 [M+H]⁺, starting from2,3-dihydro-5-methoxy-1H-inden-4-ol,

g)3-[(7-Bromo-2,3-dihydro-1H-inden-4-yl)oxy]-1-(diphenylmethyl)-azetidine,M.S. (C.I.) (M/Z): 435 [M+H]⁺, starting from7-bromo-2,3-dihydro-1H-inden-4-ol,

h)1-(Diphenylmethyl)-3-[(6-fluoro-2,3-dihydro-1-methyl-1H-inden-4-yl)oxy]-azetidine,M.S. (C.I.) (M/Z): 388 [M+H]⁺, starting from6-fluoro-2,3-dihydro-1-methyl-1H-inden-4-ol,

i)3-[(2,3-Dihydro-5-methyl-1H-inden-4-yl)oxy]-1-(diphenylmethyl)-azetidine,M.S. (C.I.) (M/Z): 370 [M+H]⁺, starting from2,3-dihydro-5-methyl-1H-inden-4-ol,

j) 1-(Diphenylmethyl)-3-[(2,3-dihydro-1H-inden-4-yl)oxy]-azetidine, M.S.(C.I.) (M/Z): 356 [M+H]⁺, starting from 2,3-dihydro-1H-inden-4-ol,

k) 3-[(Benzo(b)thien-4-yl)-1-(diphenylmethyl)-azetidine, M.S. (C.I.)(M/Z): 372 [M+H]⁺, starting from benzo(b)thiophene-4-ol,

l) 5-(3-Azetidinyloxy)-1-(diphenylmethyl)-isoquinoline, M.S. (C.I.)(M/Z): 367 [M+H]⁺, starting from 5-hydroxyisoquinoline,

m) 8-(3-Azetidinyloxy)-1-(diphenylmethyl)-quinoline, M.S. (C.I.) (M/Z):371 [M+H]⁺, starting from 8-hydroxyquinoline.

Example 2

1-(Diphenylmethyl)-3-(1-naphtalenyloxy)-azetidine hydrochloride

a) Under nitrogen 1.44 g of 1-naphtol were added to a solution of 3.37 gof potassium tert-butoxide in 71 ml tert-butanol. After stirring forhalf an hour 4.33 g of 1-(diphenylmethyl)-3-methanesulfonyloxy-azetidinemaleate were added. To increase the solubility 71 ml of dimethylsulfoxide were added. The mixture was heated in an oil bath at 80° C.for 40 hours. t-Butanol was distilled off in vacuo and the residuepartitioned between water and ethyl acetate. The ethyl acetate extractswere washed with water, dried over magnesium sulfate, filtered andevaporated in vacuo. The residue was chromatographated with toluenegiving 2.7 g of the desired product. This was treated with a solution ofhydrochloric acid in methanol, evaporated in vacuo and crystallized fromethanol absolute, yielding 2.09 g of1-(diphenylmethyl)-3-(1-naphtalenyloxy)-azetidine hydrochloride, m.p.182° C.

In a similar way were prepared:

b) 1-(Diphenylmethyl)-3-[(2-methyl-1-naphthalenyl)oxy]-azetidine, M.S.(C.I.) (M/Z): 380 [M+H]⁺, starting from 2-methyl-1-naphtol,

c) 1-(Diphenylmethyl)-3-[(4-methoxy-1-naphthalenyl)oxy]-azetidine, M.S.(C.I.) M/Z): 396 [M+H]⁺, starting from 4-methoxy-1-naphthol,

d) 1-(Diphenylmethyl)-3-(1-naphthalenylthio)-azetidine, M.S. (C.I.)(M/Z): 382 [M+H]⁺, starting from 1-naphthalenethiol,

e) 1-(Diphenylmethyl)-3-(2-naphthalenyloxy)-azetidine, M.S. (C.I.)(M/Z): 366 [M+H]⁺, starting from 2-naphthol.

Example 3

1-(Diphenylmethyl)-3-[(2-methoxy-1-naphthalenyl)oxy]-azetidinehydrochloride

a) A stirred mixture of 6.89 g of 1-(diphenylmethyl)-3-azetidinol, 25 mlanhydrous dimethyl formamide, 10.37 g potassium carbonate, 5.93 g1-bromo-2-methoxynaphtalene and 200 mg of activated copper was heatedfor 40 hours in an oil bath of 170° C. The reaction mixture waspartitioned between water and toluene. The crude product mixture fromthe organic extracts was chromatographated with toluene andtoluene/ethyl acetate (95:5). The desired product was dissolved indiethyl ether and precipitated by the addition of a solution ofhydrochloric acid in methanol. Yield: 1.96 g of1-(diphenylmethyl)-3-[(2-methoxy-1-naphtalenyl)oxy]-azetidinehydrochloride, M.S. (C.I.) (M/Z): 400 [M+H]⁺.

In a similar way was prepared:

b)1-(Diphenylmethyl)-3-[(2-(methoxymethyl)-1-naphthalenyl)oxy]-azetidinehydrochloride, M.S. (C.I.) (M/Z): 410 [M+H]⁺, starting from1-bromo-2-(methoxymethyl)-naphthalene.

Example 4

3-[(2,3-Dihydro-1H-inden4-yl)oxy]-azetidine hydrochloride

a) To a suspension of 3 g of3-[(2,3-dihydro-1H-inden-4-yl)oxy]-1-(diphenylmethyl)-azetidinehydrochloride in 250 ml ethanol were added 600 mg of palladium hydroxydeon carbon powder and the mixture was hydrogenated in a Parr apparatus at60 psi during 16 hours. After removal of the catalyst and evaporation ofthe solvent in vacuo the residue was washed several times with diethylether and decanted to remove the diphenylmethane formed. The remainingsolid was crystallized from ethanoudiethyl ether, yielding 1.27 g of3-[(2,3-dihydro-1H-inden-4-yl)oxy]-azetidine hydrochloride, m.p. 65° C.

In a similar way were prepared:

b) 3-[(2-Methyl-1-naphthalenyl)oxy]-azetidine hydrochloride, mp 171° C.starting from1-(diphenylmethyl)-3-[(2-methyl-1-naphtalenyl)oxy]-azetidine,

c) 3-(1-Naphthalenyloxy)-azetidine hydrochloride, mp 292° C. startingfrom 1-(diphenylmethyl)-3-[(1-naphtalenyl)oxy]-azetidine,

d) 3-[(4-Methoxy-1-naphthalenyl)oxy]-azetidine hydrochloride, mp 198° C.starting from1-(diphenylmethyl)-3-[(4-methoxy-1-naphtalenyl)oxy]-azetidine,

e) 3-[(5,6,7,8-Tetrahydro-1-naphthalenyl)oxy]-azetidine hydrochloride,mp 187° C. starting from1-(diphenylmethyl)-3-[(5,6,7,8-tetrahydro-1-naphtalenyl)oxy]-azetidine,

f) 3-[(5,6,7,8-Tetrahydro-2-methoxy-1-naphthalenyl)oxy]-azetidinehydrochloride, mp 164° C. starting from1-(diphenylmethyl)-3-[(2-methoxy-1-naphtalenyl)oxy]-azetidine,

g) 3-(2-Naphthalenyloxy)-azetidine hydrochloride, mp 168° C. startingfrom 1-(diphenylmethyl)-3-(²-naphtalenyloxy)-azetidine

h) 8-(3-Azetidinyloxy)-1,2,3,4-tetrahydroquinoline hydrochloride,mp>250° C. starting from8-(3-Azetidinyloxy)-1-(diphenylmethyl)-quinoline.

Example 5

3-[(5-Chloro-2,3-dihydro-1H-inden-4-yl)oxy]-azetidine hydrochloride

a) 4.22 g of3-[(5-chloro-2,3-dihydro-1H-inden-4-yl)oxy]-1-((diphenylmethyl))-azetidinewere dissolved in 71 ml of 1,2-dichloroethane. 1.58 g of 1-chloroethylchloroformate was added. The mixture was refluxed in an oil bath at 120°C. for 2.5 hours. After evaporation in vacuo the residue was refluxed in71 ml of anhydrous methanol for 2 hours. Evaporation in vacuo gave asemi solid that was stirred with diethyl ether and filtered. The solidwas recrystallized from ethanol/diethyl ether, yielding 1.57 g of3-[(5-chloro-2,3-dihydro-1H-inden-4-yl)oxy]-azetidine hydrochloride,m.p. 188° C.

In a similar way were prepared:

b) 3-[(2,4-Dichloro-1-naphthalenyl)oxy]-azetidine hydrochloride, mp 187°C. starting from3-[(2,4-Dichloro-1-naphtalenyl)oxy]-1-(diphenylmethyl)-azetidine,

c) 3-[(4-Methyl-1-naphthalenyl)oxy]-azetidine hydrochloride, mp 180° C.starting from1-(diphenylmethyl)-3-[(4-methyl-1-naphtalenyl)oxy]-azetidine,

d) 3-[(2,3-Dihydro -5-methoxy-1H-inden-4-yl)oxy]-azetidinehydrochloride, mp 166° C. starting from1-(diphenylmethyl)-3-[(2,3-dihydro-5-methoxy-1H-inden-4-yl)oxy]-azetidine,

e) 3-[(7-Bromo-2,3-dihydro-1H-inden-4-yl)oxy]-azetidine hydrochloride,mp 203° C. starting from3-[(7-bromo-2,3-dihydro-1H-inden-4-yl)oxy]-1-(diphenylmethyl)-azetidine,

f) 3-[(6-Fluoro-2,3-dihydro-1-methyl-1H-inden-4-yl)oxy]-azetidinehydrochloride, mp 170° C. starting from1-(diphenylmethyl)-3-[(6-fluoro-2,3-dihydro-1-methyl-1H-inden-4-yl)oxy]-azetidine,

g) 3-[(2,3-Dihydro-5-methyl-1H-inden-4-yl)oxy]-azetidine hydrochloridemp 184° C. starting from1-(diphenylmethyl)-3-[(2,3-dihydro-5-methyl-1H-inden-4-yl)oxy]-azetidine,

h) 3-[(Benzo[b]thien-4-yl)oxy]-azetidine hydrochloride, mp 203° C.starting from 3-[(benzo[b]thien-4-yl)oxy]-1-(diphenylmethyl)-azetidine,

i) 5-(3-Azetidinyloxy)-isoquinoline dihydrochloride, mp 198° C. startingfrom 5-(3-azetidinyloxy)-1-(diphenylmethyl)-isoquinoline.

Example 6

3-[(2-Methoxy-1-naphthalenyl)oxy]-azetidine hydrochloride

a) To a solution of 2.07 g of1-(diphenylmethyl)-3-[(2-methoxy-1-naphtalenyl)oxy]-azetidine as thatfree base in 20 ml 1,2-dichiloroethane at −15° C. was added dropwise asolution of 0.58 ml vinyloxy carbonylchloride in 20 ml1,2-dichloroethane over 15 minutes and the reaction was kept at thistemperature for another half hour. After 16 hours at ambient temperatureethanol was added from a dropping funnel. The reaction mixture wasevaporated in vacuo and the residue was purified by chromatography usingtoluene/ethyl acetate (95:5) to afford 1.55 g of a solid which wasdissolved in 25 ml of a 2M hydrochloric acid/methanol solution. Afterstanding at ambient temperature for 16 hours the solution was evaporatedin vacuo and the product crystallized from ethanol/diethyl ether.Isolated 1.02 g of 3-[(2-methoxy-1-naphtalenyl)oxy]-azetidinehydrochloride m.p. 187° C.

In a similar way were prepared:

b) 3-(1-Naphthalenylthio)-azetidine hydrochloride, mp 159° C. startingfrom 1-(diphenylmethyl)-3-(1-naphtalenylthio)-azetidine,

c) 3-[(2-(Methoxymethyl)-1-naphthalenyl)oxy]-azetidine hydrochloride, mp127° C. starting from1-(diphenylmethyl)-3-[(2-(methoxymethyl)-1-naphtalenyl)oxy]-azetidine.

Example 7

(R)-3-methanesulfonyloxy-1-(phenylmethyl)-pyrrolidine

a) 10 g of (R)-1-(phenylmethyl)-3-pyrrolidinol were dissolved in 160 mlof anhydrous toluene. The solution was stirred under a stream ofnitrogen, cooled in an ice/ethanol bath and 8.7 ml of triethylamine wereadded. At a temperature of −5° C. 4,9 ml of a solution ofmethanesulfonylchloride in 110 ml of anhydrous toluene were addeddropwise over 1,5 hours and the reaction mixture was stirred for 1 hourat 0° C. The solid was filtered and washed with ethyl acetate. Thefiltrate was washed with water, dried and evaporated in vacuo to give13,9 g of (R)-3-methanesulfonyloxy-1-(phenylmethyl)-pyrrolidine as analmost colourless oil. M.S. (C.I.) (M/Z): 256 [M+H]⁺.

In a similar way were prepared:

b) (S)-3-methanesulfonyloxy-1-(phenylmethyl)-pyrrolidine, M.S. (C.I.)(M/Z): 256 [M+H]⁺, starting from (S)-1-(phenylmethyl)-3-pyrrolidinol,

c) (rac)-3-methanesulfonyloxy-1-(phenylmethyl)-pyrrolidine, M.S. (C.I)(M/Z): 256 [M+H]⁺, starting from (rac)-1-(phenylmethyl)-3-pyrrolidinol.

Example 8

(S)-3-[(2,3-dihydro-5-methoxy-1H-inden-4-yl)oxy]-1-(phenylmethyl)-pyrrolidine

a) In 540 ml of anhydrous dimethylformamide 5 g of2,3-dihydro-5-methoxy-1H-inden-4-ol were dissolved. The solution wasstirred, placed under a steam of nitrogen and 1.5 g of a 60% dispersionof sodium hydride in oil was added. The reaction mixture was stirred atroom temperature for half an hour. The temperature was raised to 100° C.and a solution of 7.78 g of(R)-3-methanesulfonyloxy-1-(phenylmethyl)-pyrrolidine in 78 ml ofanhydrous dimethylformamide was added dropwise over 1 hour. Another 3,0g of mesylate in 30 ml of anhydrous dimethylformamide were addeddropwise over 0.5 hours and the reaction continued for another 1.5 hoursat 100° C. Evaporation in vacuo gave a semi solid that was partitionedbetween water and ethyl acetate. The ethyl acetate extract was dried andevaporated in vacuo. The derived product was isolated by chromatographyover silica using toluene/-ethanol as the eluent giving 9.45 g of(S)-3-[(2,3-dihydro-5-methoxy-1H-inden-4-yl)oxy]-1-(phenylmethyl)-pyrrolidineas an oil. M.S. (C.I.) (M/Z): 324 [M+H]⁺.

In a similar way were prepared

b)(R)-3-[(2,3-dihydro-5-methoxy-1H-inden-4-yl)oxy]-1-(phenylmethyl)-pyrrolidine,M.S. (C.I.) (M/Z): 324 [M+H]⁺, starting from2,3-dihydro-5-methoxy-1H-inden-4-ol and(S)-3-methanesulfonyloxy-1-(phenylmethyl)-pyrrolidine,

c)(rac)-3-[(2,3-Dihydro-5-methoxy-1H-inden-4-yl)oxy]-1-(phenylmethyl-pyrrolidineM.S. (C.I.) (M/Z):324 [M+H]⁺, starting from2,3-dihydro-5-methoxy-1H-inden-4-ol and(rac)-3-methanesulfonyloxy-1-(phenylmethyl)-pyrrolidine,

d) 3-(1-Naphthalenyloxy)-1-(phenylmethyl)-pyrrolidine M.S. (C.I.) (M/Z):304 [M+H]⁺, starting from 1-naphtol,

e)3-[(5,6,7,8-Tetrahydro-1-naphthalenyl)oxy]-1-(phenylmethyl)-pyrrolidine,M.S. (C.I.) (M/Z): 308 [M+H]⁺, starting from5,6,7,8-tetrahydro-1-naphthol.

Example 9

(S)-(+)-3-[(2,3-Dihydro-5-methoxy-1H-inden-4-yl)oxy]-pyrrolidinehydrochloride

a) 9.4 g of(S)-3-[(2,3-dihydro-5-methoxy-1H-inden-4-yl)oxy]-1-(phenylmethyl)-pyrrolidinewere dissolved in 300 ml of anhydrous methanol and 2,0 g of palladiumhydroxyde on carbon added. The mixture was hydrogenated in a Parrapparatus for 16 hours at 50 psi. The catalyst was filtered overdicalite and washed with methanol. The filtrate was concentrated to itsoriginal volume and 1 g of fresh palladium hydroxide or carbon wasadded. Hydrogenation was continued for 3 hours. The catalyst was removedagain and the filtrate treated with excess of a 1M hydrochloricacid/diethyl ether solution. Evaporation and crystallization formmethanol/ethyl acetate/diethyl ether gave coloured crystals that wherewashed with acetone and diethyl ether giving 3,95 g of(S)-(+)-3-[(2,3-dihydro-5-methoxy-1H-inden-4-yl)oxy]-pyrrolidinehydrochloride, m.p. 176° C.

In a similar way was prepared:

b) 3-[(5,6,7,8-Tetrahydro-1-naphthalenyl)oxy]-pyrrolidine hydrochloridem.p. 207° C., starting from3-[(5,6,7,8-tetrahydro-1-naphthalenyl)oxy]-1-(phenylmethyl)-pyrrolidine

Example 10

(R)-(−)-3-[(2,3-Dihydro-5-methoxy-1H-inden-4-yl)oxy]-pyrrolidinehydrochloride

a) 800 mg of(R)-3-[(2,3-dihydro-5-methoxy-1H-inden-4-yl)oxy]-1-(phenylmethyl)-pyrrolidinewere dissolved in 150 ml of anhydrous methanol and 1.5 equivalent ofhydrochlorid acid solved in ethyl acetate was added. Approximately 80 mgof palladium on carbon 10% were added and a stream of hydrogen waspassed through the stirred mixture. After 24 hours new catalyst wasadded and hydrogenation continued for 17 hours. The catalyst was removedby filtration, the filtrate evaporated in vacuo and the productcrystallized from ethanol/ethyl acetate/diethyl ether yielding 360 mg of(R)-(−)-3-[(2,3-dihydro-5-methoxy-1H-inden-4-yl)oxy]-pyrrolidinehydrochloride m.p. 174° C.

In a similar way were prepared:

b) (rac)-3-[(2,3-Dihydro-5-methoxy-1H-inden-4-yl)oxy] pyrrolidinehydrochloride m.p. 154° C., starting from(rac)-3-[(2,3-dihydro-5-methoxy-1H-inden-4y1)oxy]-1-(phenylmethyl)pyrrolidine,

c) (rac)-3-[(1-Naphtalenyl)oxy]pyrrolidine hydrochloride m.p. 222° C.,starting from (rac)-3-[(1-naphtalenyl)oxy]-1-(phenylmethyl)-pyrrolidine.

Example 11

(+)-3-[(1-Naphtalenyl)oxy]-pyrrolidine hydrochloride

(−)-3-[(1-Naphtalenyl)oxy]-pyrrolidine hydrochloride

3-[(1-Naphtalenyl)oxy]-pyrrolidine (80 mg) was separated by preparativechiral HPLC into the separate enantiomers. Separation was performed atroom temperature on a Chiracel OD column 240×4.6 mm with hexane/ethanol(80:20) and 0.15% diethylamine, flow 1 ml/minute.(+)-3-[(1-Naphtalenyl)oxy]-pyrrolidine was collected at t_(R) 7.4minutes, (−)-3-[(1-Naphthalenyl)oxy]-pyrrolidine was collected at t_(R)9.8 minutes.

The solutions were immediately evaporated in vacuo and converted totheir hydrochloride salts to give 10 mg of each. Estimatedenantio-purity for both these enantiomers >99.5%

TESTS

The activity of the compounds in the invention on the central nervoussystem was indicated using the pharmacological tests below; these testsdemonstrate the serotonergic activity and antidepressant-like effects ofthe invention.

BINDING TESTS

The tests are carried out using cloned human receptors expressed in 3T3cells according to the protocols described in Stam et al “Genomicorganization, coding sequence and functional expression of human 5-HT2and 5-HT1A receptor genes”—European Journal of Pharmacology—MolecularPharmacology Section 227: 153-162 (1993) and Stam et al “Genomicorganisation and functional expression of the gene encoding the humanserotonin 5-HT2C receptor”—European Journal of Pharmacology—MolecularPharmacology Section 269: 339-348 (1994). The affinity for the 5-HT2Aand 5-HT2C receptors is determined by the capacity of the compounds todisplace [3H]-ketanserin and [3H]-mesulergine from the appropriatereceptor.

PENILE ERECTION TEST

This test, carried out according to the protocol of Berendsen et al [“Involvement of 5-HT1C receptors in drug-induced penile erections inrats”—Psychopharmacology 101: 57-61(1990)] enables the potential in vivoactivity at 5HT2C receptors to be assessed.

DRL-72 TEST

This test, carried out according to the protocol of Andrews et al[“Effects of imipramine and mirtazapine on operant performance inrats”—Drug Development Research 32: 58-66 (1994)], gives an indicationof potential antidepressant-like activity.

Increase in pellets Binding pKi Erection of the penis earned in DRL-72Compound 5HT2A 5HT2C (MED, mg. kg-1) (MED, mg. kg-1) 5d 6.4 7.5 1 1010b  6.3 7.6 1 10 9a 6.8 8 0.46  3

The results show that the compounds of this invention have a greateraffinity for human 5-HT2C than for human 5-HT2A receptors, and that thisaffinity correlates with agonist activity in vivo as well as withantidepressant-like activity in an animal model for antidepressantefficacy.

What is claimed is:
 1. A compound of the formula

wherein A is a saturated or unsaturated, non-heterocyclic 5-memberedring; R¹, R² and R³ are independently H, (1-6C)alkyl, (1-6C)alkoxy,(1-6C)alkoxy-(1-6C)aklyl, carbo(1-6C)alkoxy or halogen; X is O or S; andn is 2 or a pharmaceutically acceptable salt thereof.
 2. The compoundaccording to claim 1, wherein R¹ is H, (1-6C)alkyl, (1-6C)alkoxy or(1-6C)alkoxy-(1-6C)alkyl; R² is H, (1-6C)alkoxy, carbo(1-6C)alkoxy orhalogen, and R³ is H, (1-6C)alkyl,(1-6C)alkoxy or halogen.
 3. Thecompound according to claim 1, wherein A is an unsubstituted, saturated,non-heterocyclic 5-membered ring; R¹ is H or (1-6C)alkoxy; R² is H,(1-6C)alkoxy or halogen; and R³ is H or halogen.
 4. The compound ofclaim 3, wherein A is an unsubstituted, saturated, non-heterocyclic5-membered ring; R¹ is (1-6C)alkoxy and R² and R³ are H.
 5. The compoundof claim 4, wherein A a is non-heterocyclic 5-membered ring and R¹ ismethoxy.
 6. The compound of claim 1, wherein A is substituted with oxoor (1-6C)alkyl.
 7. A pharmaceutical composition comprising an effectiveamount of the compound of claim 1 for 5-HT2C receptor agonist activityand pharmaceutically suitable auxiliaries.
 8. A method for achieving5-HT2C agonist activity in a patient, in need thereof comprisingadministering an effective amount of the compound of claim 1 to thepatient.
 9. The compound of claim 1, wherein X is O, R¹ is methoxy, andR² and R³ are H.